The primary function of the immune system is the recognition and elimination of cellular and noncellular entities which are non-self (bacteria, viruses, protozoa), or altered self, (transformed malignant cells), which would otherwise compromise health. It has been established that environmental contaminants, including the halogenated aromatic hydrocarbons TCDD and PCBs, cause immune dysfunction; however, the mechanisms are unresolved. Recently, a cytoplasmic receptor protein has been described which is a product of the Ah gene complex and which has high affinity for TCDD. Evidence indicates that TCDD toxicity and cytochrome P-450 induction segregate with the Ah complex in mice. Based on structural similarities of certain PCB congeners with TCDD, it is proposed that i.) PCB immunotoxicity is mediated through the Ah gene complex, ii.) PCB stereochemistry is critical in the development of immunotoxicity, iii.) immunotoxicity is associated not only with increased drug metabolizing activity of cytochrome P-450 isozymes, but also with other Ah structural gene protein products, and iv.) splenic cytochrome P-450 is associated with PCB immunotoxicity. These hypotheses will be tested by assessing several parameters of humoral and cellular immunity in Ah complex positive or negative mice. these parameters will be assessed following acute and subacute exposure to purified PCB congeners with different structural conformations. The role of cytochrome P-450 metabolic activity in PCB immunotoxicity will also be investigated. These investigations will incorporate techniques of immunology, toxicology, and biochemistry and will clarify the mechanisms by which halogenated aromatic hydrocarbons interfere with immune responsiveness.